title: Stabilization of physical RAF/14-3-3 interaction by cotylenin A as treatment strategy for RAS mutant cancers.
abstract: One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote the growth of RAS mutant tumors, partly due to the complex interplay between different homo- and heterodimers of A-RAF, B-RAF, and C-RAF. Based on pathway analysis and structure-guided compound identification, we describe the natural product cotylenin-A (CN-A) as stabilizer of the physical interaction of C-RAF with 14-3-3 proteins. CN-A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259, but not to the activating interaction site, pSer621. While CN-A alone is inactive in RAS mutant cancer models, combined treatment with CN-A and an anti-EGFR antibody synergistically suppresses tumor growth in vitro and in vivo. This defines a novel pharmacologic strategy for treatment of RAS mutant cancers.
authors.affiliation: Chemical Genomics Centre of the Max-Planck-Society , Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Molzan
authors.forename: Stefan
authors.initials: S
authors.lastname: Kasper
authors.forename: Lars
authors.initials: L
authors.lastname: Röglin
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Skwarczynska
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sassa
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Inoue
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D060066:Protein Interaction Maps / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D001688:Biological Products; D004224:Diterpenes; C423222:cotylenin A; D019908:Proto-Oncogene Proteins c-raf; D048490:raf Kinases; D018631:ras Proteins